The VPR gene from HIV-1 encodes a 96 amino acid protein that induces apoptosis in infected lymphocytes. VPR induces apoptosis independently of the presence and function of p53, and in a manner that is mediated by activation of the cystine-aspartate proteases 3 and 8. The objective of the present study is to understand at a molecular level the mechanisms by which HIV-1 VPR induces apoptosis. Studies will first examine the possibility that VPR activates apoptosis pathways that normally function in response to death receptor activation or DNA damage. Studies will next be conducted to examine the degree of activation or inactivation of survival pathw0ays that normally prevent entry into apoptosis. Macrophages will then be examined to determine the impact of long-term, chronic infection by HIV-1 and the relationship to apoptosis. And lastly, studies will examine patterns of gene expression in an attempt to identify undefined cellular genes whose transcription is modified during VPR induced apoptosis. Specific aims of this proposal are: aim 1. To define the apoptosis signaling cascade that is activated by VPR. Aim 2. To examine the role of the survival pathway in VPR induced apoptosis. Aim 3. To examine the effect of VPR on the viability of primary macrophages. Aim 4. To identify differentially expressed cellular genes during VPR induced apoptosis.